Chronic heart failure (CHF) is a serious and debilitating condition with poor survival rates and an increasing level of prevalence. Exaggerated sympatho-excitation, that is a hallmark of CHF, is a critical factor in the development and progression of CHF. Sympatho-excitation targets multiple organs and causes long-term effects that contribute to disease progression. The mechanism(s) by which sympathetic excitation occurs in the CHF state are not completely understood.
Myocardial ischemia causes the production and release of several metabolites including bradykinin, prostaglandins and protons that stimulate sympathetic afferent nerve endings. This leads to increases in arterial pressure (AP), heart rate (FIR) and sympathetic nerve activity (Wang and Zucker, Am. J. Physiol. 1996, 271:R751-R756; Wang and Ma, Heart Fail Rev. 2000; 5:57-71; and Longhurst et al. Ann. NY Acad. Sci. 2001; 940:74-95). In CHF, the CSAR is sensitized and cardiac sympathetic afferents are tonically activated (Wang and Zucker, Am. J. Physiol. 1996 271:R751-R756; Gao et al. Hypertension. 2005; 45:1173-1181; and Wang and Ma, Heart Fail Rev. 2000; 5:57-71).
Increased cardiac sympathetic nerve activity is a primary characteristic of patients suffering from CHF (Lohse et al. Circ. Res. 2003; 93:896-906; and Hasking et al. Circulation. 1986; 73:615-621). Prolonged stimulation of the f3-adrenergic neurohormonal axis has been shown to contribute to the progression of CHF and mortality in both animal models and in humans (Singh et al. Cardiovasc. Res. 2000; 45:713-719; and Fowler et al. Circulation. 1986; 74:1290-1302). Measurements of cardiac NE spillover in CHF patients reflecting cardiac sympathetic nerve activity, indicate that it is increased earlier and to a greater extent than sympathetic nerve activity to other organs (Ramchandra et al. Proc. Natl. Acad. Sci. USA. 2009; 106:924-928; Meredith et al. N. Engl. J. Med. 1991; 325:618-624; and Rundqvist et al. Circulation. 1997; 95:169-175). One potential explanation is an increased CSAR control of cardiac sympathetic efferent outflow (also called the “cardiac-cardiac reflex”) in CHF.
Myocardial ischemia releases large amounts of metabolites including bradykinin, ATP, prostaglandins and protons that stimulate cardiac sympathetic afferent nerve endings and cause an excitatory response of MAP, HR and sympathetic nerve activity. Acute epicardial application of lidocaine, which blocked cardiac sympathetic afferent input, decreased baseline MAP, HR and RSNA in anesthetized CHF dogs and rats but not in sham animals, indicating that the CSAR is tonically activated and contributes to the elevated renal sympathetic nerve activity in CHF. The sites at which the CSAR is sensitized reside at both the afferent endings (Wang et al. Am. J. Physiol. 1999; 277:H812-H817) and in the central nervous system (Ma et al. Am. J. Physiol. 1997; 273:H2664-H2671).
Direct application of a vanilloid receptor agonist into the neuron cell body contained in a ganglion opens calcium channels in VR1-expressing neuronal perikarya, triggering a cascade of events leading to cell death. Vanilloid receptor-1 (VR1) is a multimeric cation channel prominently expressed in nociceptive primary afferent neurons (Caterina et al., Nature 89:8160824, 1997; Tominaga et al., Neuron 531-543, 1998). Activation of the receptor typically occurs at the nerve endings via application of painful heat (VR1 transduces heat pain) or during inflammation or exposure to vanilloids. Activation of VR1 by an agonist, such as resiniferatoxin or capsaicin, results in the opening of calcium channels and the transduction of pain sensation (Szalllasi et al., Mol. Pharmacol. 56:581-587, 1999.) After an initial activation of VR1, VR1 agonists desensitize VR1 to subsequent stimuli. This desensitization phenomenon has been exploited in order to produce analgesia to subsequent nociceptive challenge. For example, it has been shown that topical administration of resiniferatoxin (RTX), which is a potent vanilloid receptor agonist, at the nerve endings in the skin triggers a long-lasting insensitivity to chemical pain stimulation. Furthermore, it has been shown that both subcutaneous and epidural administration of the RTX produce thermal analgesia when administered to rats, with no restoration of pain sensitivity for over 7 days (Szabo et al., Brain Res. 840:92-98, 1999).
Resiniferatoxin (RTX) is used as the vanilloid receptor agonist. RTX is unlike structurally related phorbol esters because it acts as an ultrapotent analog of capsaicin, the pungent principle of the red pepper. RTX is a tricyclic diterpene isolated from Eurphorbia resinifera. RTX induces pain, hypothermia, and neurogenic inflammation; the acute responses are followed by desensitization to RTX and by cross-desensitization to capsaicin. A homovanillyl group is an important structural feature of capsaicin and the most prominent feature distinguishing resiniferatoxin from typical phorbol-related compounds. Naturally occurring or native RTX has the following structure:

RTX and analog compounds such as tinyatoxin as well other compounds, (20-homovanillyl esters of diterpenes such as 12-deoxyphorbol 13-phenylacetate 20-homovanillate and mezerein 20-homovanillate) are described in U.S. Pat. Nos. 4,939,194; 5,021,450; and 5,232,684, the disclosures of which are incorporated by reference herein. Other resiniferatoxin-type phorboid vanilloids have also been identified (Szallasi et al., Brit. J. Phrmacol. 128:428-434, 1999). As used herein, “a resiniferatoxin” or “an RTX” refers to naturally occurring RTX and analogs of RTX, including other phorbol vanilloids with VR1 agonist activity.
Transient receptor potential vanilloid 1 (TRPV1)-expressing cardiac afferent fibers are necessary for sensing and triggering the activation of the CSAR. Desensitizing cardiac afferents can almost completely abolish CSAR activation in adult rats (Zahner et al., J. Physiol. 2003; 551:515-523). Therefore, there is a need in the art to desensitize cardiac afferent fibers as a potential treatment for heart failure and its various related cardiovascular conditions.